Thiophene-2-carbonyl chlorides are important synthetic intermediates, for instance for the synthesis of drugs and agrochemicals. They can be prepared by a number of different routes, each having advantages and disadvantages. Of particular interest are methods that only require inexpensive starting materials and reagents, are easy to perform, and generate only small amounts of waste.
Thiophene-2-carbonyl chloride is an intermediate for the preparation of Tioxazafen, a nematicide, with CAS 330459-31-9 and with the chemical name 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole and which is the compound of formula (THIOXA-1).

WO 2014/008257 A2 discloses the preparation of compound of formula (THIOXA-1).
5-Chloro-thiophene-2-carbonyl chloride is an intermediate for the preparation of Rivaroxaban, an anti-thrombotic agent, with CAS 366789-02-8 and with the chemical name (S)-5-Chlor-N-{2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-ylmethyl}thiophen-2-carbamid and which is compound of formula (RIVA-1).
US 2003/0153610 A1 discloses Rivaroxaban and a method for its preparation, US 2015/0133657 A1 discloses another method for its preparation, U.S. Pat. No. 6,107,519 discloses certain precursors used in said preparation.
U.S. Pat. No. 4,321,399 discloses the preparation of thiophene-2-carbonyl chloride by a reaction of thiophene and phosgene in the presence of aluminum chloride and in a specific and inert organic solvent. In this method thiophene is added to a premixture of phosgene and aluminum chloride in the solvent. After the addition of thiophene the resulting mixture must be hydrolysed immediately by pouring the resulting mixture immediately into iced aqueous hydrochloric acid. The disclosure stresses the necessity of fast hydrolysis of the resulting mixture by advising a minimal continued contact of the thiophene with the premixture. Furthermore also higher concentration of thiophene are stated to have a negative effect on the yield, a content of only 5 to 10% of thiophene in the resulting mixture is advised. Therefore a continuous stream reaction is suggested in order to control these critical parameters, but such a continuous stream reaction is not disclosed. A draw back of a continuous reaction for the disclosed method is the insolubility of aluminum chloride in the solvent, because a suspension is formed which creates difficulties when conveyed by pumping through a continuous reactor set up due to clogging. Obviously when the disclosed reaction needs to be scaled up for production the disclosed “immediate hydrolysis” is no longer feasible, therefore the continuous reactor set up is actually mandatorily needed to ensure the required “immediate hydrolysis”.
Edwards et al. in J. Org. Chem. 1966, 31, 1283 to 1285, disclose on page 1284 right column second paragraph, that thiophene is sensitive to acids and polymerizes to tar upon treatment with aluminum chloride: “With thiophene, aluminum chloride, and the same anhydride, tar formation was so great that the results were meaningless”.
Also Geobaldo et al., Phys. Chem. Chem. Phys., 1999, 1, 561 to 569, warns on page 561 right column last paragraph, that thiophene is not stable under acidic conditions and is prone to electrophilic attack with the formation of stable oligomeric compounds.
Kuehnhanss et al., Journal für Praktische Chemie, 1956, 3, 137 to 145, reports specifically on page 144 a reaction of thiophene with oxalyl chloride at reflux temperature, which is below the boiling point of 61° C. for oxalyl chloride and of 84° C. for thiophene, followed by distillation and saponification, with a yield of 36.5% of thiophene-2-carboxylic acid. Reported on page 140 is an optimum of 60 h for the conversion, resulting in a yield of ca. 35%. Longer reaction times result in black condensation products, after 90 h no carbonyl chloride can be isolated anymore. The use of oxalyl chloride compared to the use of the carbamoyl chloride shows that oxalyl chloride has lower reactivity resulting in harder reaction conditions and lower yield (page 140), and therefore presents oxalyl chloride as a lesser attractive carboxylating agent than carbamoyl chloride. Carbamoyl chloride as carboxylating agent results in the formation of thiophene-2-carboxamide, which needs saponification with e.g. a base to provide the free acid, which again needs a conversion step to obtain the desired carbonyl chloride.
Comparative example 1 shows that even a molar excess of oxalyl choride of 5 times under the reaction conditions of Kuehnhanss did not improve the yield, but lowered the yield to ca. 9%.
There was a need for a method for preparation of thiophene-2-carbonyl chlorides that has few steps, with high yields, that does not need aluminum chloride or ammonium chloride, that does not create large amounts of salt as aluminum chloride for example would do, and that does not require mandatorily the use of a continuous reactor set up when it is scaled up for production.
Unexpectedly a method for preparation of thiophene-2-carbonyl chlorides starting from inexpensive thiophenes with oxalyl chloride was found which meets the needs mentioned above. Edwards, Geobaldo and Kuehnhanns stress the sensitivity of thiophenes against acid and its disposition to formation of oligomers and even tar at elevated temperature. Especially Kuehnhanns reports the formation of tar even at a low temperature resulting from the boiling point of oxalyl chloride. These comments discourage any treatment of thiophenes at elevated temperature above the boiling point of oxalyl chloride, especially not in the presence of acid. Contrary to this premonitions significantly higher yields compared to Kuehnhanns can be obtained at significantly higher temperatures than reported by Kuehnhanns. The purities are comparatively high, the reaction time is significantly shorter, no aluminum chloride is required, and the conversion of the thiophenes is complete. Despite the sensitivity of thiophenes towards acids, no significant amounts of byproducts are formed. Not steps such a saponification and conversion of a free acid to the acid chloride is required.
The following meanings are used,
halogen means F, Cl, Br or I, preferably Cl, Br or I, more preferably Cl or Br;
sulfolane CAS 126-33-0;
if not otherwise stated.